EP1492797B1 - 1-oxa-3-aza-dibenzoazulene als inhibitoren der produktion von tumornekrosefaktor und zwischenprodukte für deren herstellung - Google Patents

1-oxa-3-aza-dibenzoazulene als inhibitoren der produktion von tumornekrosefaktor und zwischenprodukte für deren herstellung Download PDF

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EP1492797B1
EP1492797B1 EP03745848A EP03745848A EP1492797B1 EP 1492797 B1 EP1492797 B1 EP 1492797B1 EP 03745848 A EP03745848 A EP 03745848A EP 03745848 A EP03745848 A EP 03745848A EP 1492797 B1 EP1492797 B1 EP 1492797B1
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aza
dibenzo
azulene
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compounds
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EP1492797A1 (de
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Mladen Mercep
Milan Mesic
Dijana Pesic
Iva Benko
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Fidelta doo
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • mice in which mice genes for TNF- ⁇ or its receptor were inactivated.
  • Such animals are resistant to collagen-induced arthritis (Mori L et al., J. Immunol., 1996 , 157 :3178-3182) and to endotoxin-caused shock (Pfeffer K et al., Cell, 1993 , 73 :457-467).
  • Novel approaches in the therapy of rheumatoid arthritis are based upon drugs such as tenidap, leflunomide, cyclosporin, FK-506 and upon biomolecules neutralizing the TNF- ⁇ action.
  • drugs such as tenidap, leflunomide, cyclosporin, FK-506 and upon biomolecules neutralizing the TNF- ⁇ action.
  • etanercept Enbrel, Immunex/Wyeth
  • a fusion protein of the soluble TNF- ⁇ receptor a chimeric monoclonal human and mouse antibody infliximab (Remicade, Centocor).
  • etanercept and infliximab are also registered for the therapy of Crohn's disease ( Exp. Opin. Invest. Drugs, 2000, 9 :103).
  • IL-1RII transfers a signal intracellularly
  • IL-1RII is situated on the cell surface and does not transfer a signal inside the cell. Since IL1-RII binds IL-1 as well as IL1-RI, it may act as a negative regulator of IL-1 action. Besides this mechanism of signal transfer regulation, another natural antagonist of IL-1 receptor (IL-Ira) is present in cells. This protein binds to IL-1RI but does not transfer any signal. However, its potency in stopping the signal transfer is not high and its concentration has to be 500 times higher than that of IL-1 in order to achieve a break in the signal transfer.
  • IL-Ira another natural antagonist of IL-1 receptor
  • the present invention relates to 1-oxa-3-aza-dibenzoazulenes of the formula I wherein
  • halo halogen atom which may be fluorine, chlorine, bromine or iodine.
  • alkoxy relates to straight or branched chains of alkoxy group. Examples of such groups are methoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy.
  • aryl relates to groups having the meaning of an aromatic ring, e.g. phenyl, as well as to fused aromatic rings.
  • Aryl contains one ring with at least 6 carbon atoms or two rings with totally 10 carbon atoms and with alternating double (resonant) bonds between carbon atoms.
  • the most freqently used aryls are e.g. phenyl or naphthyl.
  • aryl groups may be linked to the rest of the molecule by any available carbon atom via a direct bond or via a C 1 -C 4 alkylene group such as methylene or ethylene.
  • alkyl relates to alkyl groups which may be optionally additionally substituted with one, two, three or more substituents.
  • substituents may be halogen atom (preferably fluorine, chlorine or bromine), hydroxy, C 1 -C 4 alkoxy (preferably methoxy or ethoxy), thiol, C 1 -C 4 alkylthio (preferably methylthio or ethylthio), amino, N -(C 1 -C 4 ) alkylamino (preferably N -methylamino or N -ethylamino), N,N di(C 1 -C 4 -alkyl)-amino (preferably dimethylamino or diethylamino), sulfonyl, C 1 -C 4 alkylsulfonyl (preferably methylsulfonyl or ethylsulfonyl), sulfinyl, C 1 -C 4 alkylsulf

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pulmonology (AREA)
  • Toxicology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Claims (15)

  1. Verbindung der Formel I
    Figure imgb0031
    worin
    X für ein Heteroatom wie O, S, S(=O), S(=O)2, oder NRa , worin Ra Wasserstoff oder eine Schutzgruppe bedeutet, stehen kann;
    Y und Z unabhängig voneinander einen oder mehrere gleiche oder verschiedene, an jedes verfügbare Kohlenstoffatom gebundene Substituenten bedeuten und für Wasserstoff, Halogen, C1-C4-Alkyl, C2-C4-Alkenyl, C2-C4-Alkinyl, Halogen-C1-C4-alkyl, Hydroxy, C1-C4-Alkoxy, Trifluormethyl, Trifluormethoxy, C1-C4-Alkanoyl, Amino, Amino-C1-C4-alkyl, N-(C1-C4-Alkyl)amino, N,N-Di(C1-C4-Alkyl)amino, Thiol, C1-C4-Alkylthio, Sulfonyl, C1-C4-Alkylsulfonyl, Sulfinyl, C1-C4-Alkylsulfinyl, Carboxy, C1-C4-Alkoxycarbonyl, Cyano, Nitro stehen können;
    R1 für Wasserstoff, C1-C7-Alkyl, CHO, (CH2)2COOH, (CH2)2CO2Et, (CH2)mL, worin m die Bedeutung von 1 oder 3 hat und L die Bedeutung von OH oder Br hat; oder für einen Substituenten der Formel II
    Figure imgb0032

    stehen kann,
    worin
    R2 und R3 gleichzeitig oder unabhängig voneinander für Wasserstoff, C1-C4 Alkyl, Aryl stehen können oder zusammen mit N die Bedeutung von gegebenenfalls substituiertem Heterozyklus oder Heteroaryl haben;
    m eine Ganzzahl von 1 bis 3 darstellt;
    n eine Ganzzahl von 0 bis 3 darstellt;
    Q1 und Q2 unabhängig voneinander Sauerstoff, Schwefel oder Gruppen:
    Figure imgb0033
    Figure imgb0034

    darstellen, worin die Substituenten
    y1 und y2 unabhängig voneinander für Wasserstoff, Halogen, C1-C4-Alkyl oder Aryl, Hydroxy, C1-C4-Alkoxy, C1-C4-Alkanoyl, Thiol, C1-C4-Alkylthio, Sulfonyl, C1-C4-Alkylsulfonyl, Sulfinyl, C1-C4-Alkylsulfinyl, Cyano, Nitro stehen können oder zusammen Carbonyl- oder Iminogruppe bilden;
    sowie deren pharmakologisch annehmbare Salze und Solvate,
    worin für alle vorgenannten Substituenten Aryl eine Gruppe ist, die die Bedeutung von einem aromatischen Ring sowie von kondensierten aromatischen Ringen, die einen Ring mit mindestens 6 Kohlenstoffatomen oder zwei Ringe mit insgesamt 10 Kohlenstoffatomen und mit alternierenden Doppelbindungen zwischen Kohlenstoffatomen enthalten, hat; worin Heteroaryl eine Gruppe ist, die die Bedeutung von aromatischer oder teilweise aromatischer Gruppe eines monozyklischen oder bizyklischen Rings mit 4 bis 12 Atomen hat, wobei mindestens einer von ihnen ein Heteroatom wie O, S oder N ist; worin Heterozyklus eine fünfgliedrige oder sechsgliedrige, völlig gesättigte oder teilweise ungesättigte heterozyklische Gruppe enthaltend mindestens ein Heteroatom wie O, S oder N bedeutet; und worin ein gegebenenfalls substituiertes Heteroaryl oder Heterozyklus eine Heteroaryl- oder heterozyklische Gruppe bedeutet, die mit einem oder zwei Substituenten, die Halogen, C1-C4-Alkyl, Cyano, Nitro, Hydroxy, C1-C4-Alkoxy, Thiol, C1-C4-Alkylthio, Amino, N-(C1-C4)-Alkylamino, N,N-Di(C1-C4-alkyl)-amino, Sulfonyl, C1-C4-Alkylsulfonyl, Sulfinyl, C1-C4-Alkylsulfinyl bedeuten, substituiert ist.
  2. Verbindung nach Anspruch 1, worin X für S oder O steht.
  3. Verbindung nach Anspruch 2, worin Y und/oder Z für H, Cl stehen.
  4. Verbindung und Salz nach Anspruch 3, worin R1 für H, CH3, CHO, (CH2)2COOH, (CH2)2CO2Et steht.
  5. Verbindung nach Anspruch 3, worin R1 für (CH2)mL steht.
  6. Verbindung nach Anspruch 5, worin das Symbol m die Bedeutung von 1 oder 3 hat.
  7. Verbindung nach Anspruch 6, worin L für OH oder Br steht.
  8. Verbindung und Salz nach Anspruch 3, worin R1 die Bedeutung von Formel II hat.
  9. Verbindung und Salz nach Anspruch 8, worin m die Bedeutung von 1 hat, n die Bedeutung von 1 oder 2 hat, Q1 für O steht, Q2 für CH2 steht und R1 und R für CH3 stehen.
  10. Ausgewählte Verbindungen nach Anspruch 4:
    1-Oxa-8-thia-3-aza-dibenzo[e,h]azulen;
    1,8-Dioxa-3-aza-dibenzo[e,h]azulen;
    3-(1-Oxa-8-thia-3-aza-dibenzo[e,h]azulen-2-yl)-propionsäure-Ethylester;
    3-(1,8-Dioxa-3-aza-dibenzo[e,h]azulen-2-yl)-propionsäure-Ethylester;
    2-Methyl-1-oxa-8-thia-3-aza-dibenzo[e,h]azulen;
    2-Methyl-1,8-dioxa-3-aza-dibenzo[e,h]azulen;
    11-Chlor-2-methyl-1-oxa-8-thia-3-aza-dibenzo[e,h]azulen;
    S-Chlor-2-methyl-1-oxa-8-thia-3-aza-dibenzo[e,h]azulen;
    11-Chlor-2-methyl-1,8-dioxa-3-aza-dibenzo[e,h]azulen;
    5-Chlor-2-methyl-1,8-dioxa-3-aza-dibenzo[e,h]azulen;
    1-Oxa-8-thia-3-aza-dibenzo[e,h]azulen-2-carbaldehyd;
    3-(1-Oxa-8-thia-3-aza-dibenzo[e,h]azulen-2-yl)-propionsäure;
    3-(1,8-Dioxa-3-aza-dibenzo[e,h]azulen-2-yl)-propionsäure.
  11. Ausgewählte Verbindungen nach Anspruch 7:
    (1-Oxa-8-thia-3-aza-dibenzo[e,h]azulen-2-yl)-methanol;
    3-(1-Oxa-8-thia-3-aza-dibenzo[e,h]azulen-2-yl)propan-1-ol;
    3-(1,8-Dioxa-3-aza-dibenzo[e,h]azulen-2-yl)propan-1-ol;
    2-Brommethyl-1-oxa-8-thia-3-aza-dibenzo[e,h]azulen;
    2-Brommethyl-1,8-dioxa-3-aza-dibenzo[e,h]azulen;
    2-Brommethyl-5-chdor-1-oxa-8-thia-3-aza-dibenzo[e,h]azulen;
    2-Brommethyl-11-chlor-1-oxa-8-thia-3-aza-dibenzo[e,h]azulen;
    2-Brommethyl-5-chlor-1,8-dioxa-3-aza-dibenzo[e,h]azulen;
    2-Brommethyl-11-chlor-1,8-dioxa-3-aza-dibenzo[e,h]azulen.
  12. Ausgewählte Verbindungen und Salze nach Anspruch 9:
    Dimethyl-[2-(1-oxa-8-thia-3-aza-dibenzo[e,h]azulen-2-ylmethoxy)-ethyl]-amin;
    Dimethyl-[3-(1-oxa-8-thia-3-aza-dibenzo[e,h]azulen-2-ylmethoxy)-propyl]-amin;
    Dimethyl-{2-[3-(1-oxa-8-thia-3-aza-dibenzo[e,h]azulen-2-yl)-propoxy]-ethyl}-amin;
    Dimethyl-{3-[3-(1-oxa-8-thia-3-aza-dibenzo[e,h]azulen-2-yl)-propoxy]-propyl}-amin;
    {2-[3-(1,8-Dioxa-3-aza-dibenzo[e,h]azulen-2-yl)-propoxy]-ethyl}-dimethylamin;
    (3-[3-(1,8-Dioxa-3-aza-dibenzo[e,h]azulen-2-yl)-propoxy]-propyl}-dimethylamin;
    [2-(1,8-Dioxa-3-aza-dibenzo[e,h]azulen-2-ylmethoxy)-ethyl]-dimethylamin;
    [3-(1,8-Dioxa-3-aza-dibenzo[e,h]azulen-2-ylmethoxy)-propyl]-dimethylamin;
    2-(5-Chlor-1-oxa-8-thia-3-aza-dibenzo[e,h]azulen-2-ylmethoxy)-ethyl]-dimethylamin;
    [3-(5-Chlor-1-oxa-8-thia-3-aza-dibenzo[e,h]azulen-2-ylmethoxy)-propyl]-dimethylamin;
    [2-(11-Chlor-1-oxa-8-thia-3- aza-dibenzo[e,h]azulen-2-ylmethoxy)-ethyl]-dimethylamin;
    [3-(11- Chlor-1-oxa-8-thia-3-aza-dibenzo[e,h]azulen-2-ylmethoxy)-propyl]-dimethylamin;
    (2-(5-Chlor-1,8-dioxa-3-aza-dibenzo[e,h]azulen-2-ylmethoxy)-ethyl]-dimethylamin;
    (3-(5-Chlor-1,8-dioxa-3-aza-dibenzo[e,h]azulen-2-ylmethoxy)-propyl]-dimethylamin;
    [2-(11-Chlor-1,8-dioxa-3-aza-dibenzo[e,h]azulen-2-ylmethoxy)-ethyl]-dimethylamin;
    [3-(11-Chlor-1,8-dioxa-3-aza-dibenzo[e,h]azulen-2-ylmethoxy)-propyl]-dimethylamin.
  13. Verfahren zur Herstellung von Verbindungen der Formel I
    Figure imgb0035
    worin
    X für ein Heteroatom wie O, S, S(=O), S(=O)2, oder NRa , worin Ra Wasserstoff oder eine Schutzgruppe bedeutet, stehen kann;
    Y und Z unabhängig voneinander einen oder mehrere gleiche oder verschiedene, an jedes verfügbare Kohlenstoffatom gebundene Substituenten bedeuten und für Wasserstoff, Halogen, C1-C4-Alkyl, C2-C4-Alkenyl, C2-C4-Alkinyl, Halogen-C1-C4-alkyl, Hydroxy, C1-C4-Alkoxy, Trifluormethyl, Trifluormethoxy, C1-C4-Alkanoyl, Amino, Amino-C1-C4-alkyl, N-(C1-C4-Alkyl)amino, N,N-Di(C1-C4-Alkyl)amino, Thiol, C1-C4-Alkylthio, Sulfonyl, C1-C4-Alkylsulfonyl, Sulfinyl, C1-C4-Alkylsulfinyl, Carboxy, C1-C4-Alkoxycarbonyl, Cyano, Nitro stehen können;
    R1 für Wasserstoff, C1-C7-Alkyl, CHO, (CH2)2COOH, (CH2)2CO2Et, (CH2)mL, worin m die Bedeutung von 1 oder 3 hat und L die Bedeutung von OH oder Br hat; oder einen Substituenten der Formel II
    Figure imgb0036
     stehen kann,

    worin
    R2 und R3 gleichzeitig oder unabhängig voneinander für Wasserstoff, C1-C4 Alkyl, Aryl stehen können oder zusammen mit N die Bedeutung von gegebenenfalls substituiertem Heterozyklus oder Heteroaryl haben;
    m eine Ganzzahl von 1 bis 3 darstellt;
    n eine Ganzzahl von 0 bis 3 darstellt;
    Q1 und Q2 unabhängig voneinander Sauerstoff, Schwefel oder Gruppen:
    Figure imgb0037
    Figure imgb0038

    darstellen, worin die Substituenten
    y1 und y2 unabhängig voneinander für Wasserstoff, Halogen, C1-C4-Alkyl oder Aryl, Hydroxy, C1-C4-Alkoxy, C1-C4-Alkanoyl, Thiol, C1-C4-Alkylthio, Sulfonyl, C1-C4-Alkylsulfonyl, Sulfinyl, C1-C4-Alkylsulfinyl, Cyano, Nitro stehen können oder zusammen Carbonyl- oder Iminogruppe bilden;
    sowie deren pharmakologisch annehmbaren Salzen und Solvaten,
    worin für alle vorgenannten Substituenten Aryl eine Gruppe ist, die die Bedeutung von einem aromatischen Ring sowie von kondensierten aromatischen Ringen, die einen Ring mit mindestens 6 Kohlenstoffatomen oder zwei Ringe mit insgesamt 10 Kohlenstoffatomen und mit alternierenden Doppelbindungen zwischen Kohlenstoffatomen enthalten, hat; worin Heteroaryl eine Gruppe ist, die die Bedeutung von aromatischer oder teilweise aromatischer Gruppe eines monozyklischen oder bizyklischen Rings mit 4 bis 12 Atomen hat, wobei mindestens einer von ihnen ein Heteroatom wie O, S oder N ist; worin Heterozyklus eine fünfgliedrige oder sechsgliedrige, völlig gesättigte oder teilweise ungesättigte heterozyklische Gruppe enthaltend mindestens ein Heteroatom wie O, S oder N bedeutet; und worin ein gegebenenfalls substituiertes Heteroaryl oder Heterozyklus eine Heteroaryl- oder heterozyklische Gruppe bedeutet, die mit einem oder zwei Substituenten, die Halogen, C1-C4-Alkyl, Cyano, Nitro, Hydroxy, C1-C4-Alkoxy, Thiol, C1-C4-Alkylthio, Amino, N-(C1-C4)-Alkylamino, N,N-Di(C1-C4-alkyl)-amino, Sulfonyl, C1-C4-Alkylsulfonyl, Sulfinyl, C1-C4-Alkylsulfinyl bedeuten, substituiert ist,
    dadurch gekennzeichnet, dass die Herstellungsverfahren umfassen
    a) für die Verbindungen der Formel I,
    eine Zyklisierung der Verbindungen der Formel III
    Figure imgb0039
    worin A die Bedeutung von -O- oder -NH- hat;
    b) für die Verbindungen der Formel I, worin Q1 die Bedeutung von -O- hat,
    eine Umsetzung der Alkohole der Formel IV:
    Figure imgb0040
    mit den Verbindungen der Formel V:
    Figure imgb0041
    worin R4 die Bedeutung einer Abgangsgruppe hat;
    c) für die Verbindungen der Formel I, worin Q1 die Bedeutung von -O-, -NH-, -S- oder -C≡C- hat,
    eine Umsetzung der Verbindungen der Formel IVa
    Figure imgb0042
    worin L die Bedeutung einer Abgangsgruppe hat,
    mit den Verbindungen der Formel Va
    Figure imgb0043
    d) für die Verbindungen der Formel I, worin Q1 die Bedeutung eines Heteroatoms -O-, -NH- oder -S- hat,
    eine Umsetzung der Verbindungen der Formel IVb
    Figure imgb0044
    mit den Verbindungen der Formel V, worin R4 die Bedeutung einer Abgangsgruppe hat;
    e) für die Verbindungen der Formel I, worin Q1 die Bedeutung von -C=C- hat,

    eine Umsetzung der Verbindungen der Formel IVb, worin Q1 die Bedeutung von Carbonyl hat, mit Phosphoryliden.
  14. Verwendung der Verbindungen der Formel I nach Ansprüchen 4 und 7 als Zwischenverbindungen zur Herstellung von Dibenzoazulen der Formel I mit entzündungshemmender Wirkung.
  15. Verwendung der Verbindungen der Formel I nach Ansprüch 8 zur Herstellung eines die Produktion von Cytokinen oder Entzündungsvermittlern inhibierenden Arzneimittels in der Behandlung und Prophylaxe von jeglichen pathologischen Zuständen oder Krankenheiten, die durch übermäßige unregulierte Produktion von Cytokinen oder Entzündungvermittlem induziert werden, durch perorale, parenterale oder lokale Verabreichung einer untoxischen Dosis von geeigneten pharmazeutischen Zubereitungen.
EP03745848A 2002-04-10 2003-04-09 1-oxa-3-aza-dibenzoazulene als inhibitoren der produktion von tumornekrosefaktor und zwischenprodukte für deren herstellung Expired - Lifetime EP1492797B1 (de)

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SI200330276T SI1492797T1 (sl) 2002-04-10 2003-04-09 1-oksa-3-aza-dibenzoazuleni kot inhibitorji proizvajanja faktorja tumorske nekroze in intermediati za njihovo pripravo

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HR20020304A HRP20020304B1 (en) 2002-04-10 2002-04-10 1-oxa-3-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the production thereof
HR20020304 2002-04-10
PCT/HR2003/000015 WO2003084964A1 (en) 2002-04-10 2003-04-09 1-oxa-3-aza-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the production thereof

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EP1492797B1 true EP1492797B1 (de) 2006-03-15

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US (1) US7232815B2 (de)
EP (1) EP1492797B1 (de)
JP (1) JP2005529867A (de)
CN (1) CN1649878A (de)
AT (1) ATE320434T1 (de)
AU (1) AU2003259960A1 (de)
BR (1) BR0309101A (de)
CA (1) CA2481463A1 (de)
DE (1) DE60304047T2 (de)
DK (1) DK1492797T3 (de)
ES (1) ES2260636T3 (de)
HR (1) HRP20020304B1 (de)
IL (1) IL164397A0 (de)
IS (1) IS7473A (de)
MX (1) MXPA04009944A (de)
NO (1) NO20044507L (de)
NZ (1) NZ535621A (de)
PL (1) PL372456A1 (de)
PT (1) PT1492797E (de)
RU (1) RU2323222C2 (de)
UA (1) UA79276C2 (de)
WO (1) WO2003084964A1 (de)
YU (1) YU88204A (de)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HRP20020304B1 (en) * 2002-04-10 2008-04-30 GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. 1-oxa-3-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the production thereof
DE10256416A1 (de) * 2002-12-02 2004-06-09 Basf Ag Feste Pigmentzubereitungen, enthaltend Pigmentderivate und oberflächenaktive Additive
HRP20030959A2 (de) * 2003-11-21 2005-10-31 Pliva-Istra�iva�ki institut d.o.o.
EP1844053A2 (de) * 2005-01-13 2007-10-17 GlaxoSmithKline istrazivacki centar Zagreb d.o.o. Entzündungshemmende makrolidkonjugate

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US3745167A (en) * 1968-03-19 1973-07-10 Hoffmann La Roche 3a,12b-dihydro-8h-dibenzo(3,4,6,7)cyclohept(1,2,-)oxazol-8-ones and processes for their preparation
JPS458611Y1 (de) 1969-08-18 1970-04-22
GB1340637A (en) * 1971-02-05 1973-12-12 Richardson Merrell Spa Dibenzocycloheptadioxolan derivatives
US3711489A (en) * 1971-03-31 1973-01-16 Pfizer Certain 8,9-dihydro(3,4,7,8)cycloocta(1,2-d)imidazoles
CA967573A (en) 1972-12-22 1975-05-13 Joseph G. Lombardino Tetracyclic anti-inflammatory agents
US4198421A (en) * 1978-11-30 1980-04-15 E. I. Du Pont De Nemours And Company Antiinflammatory 2-substituted-dibenzo[2,3:6,7]oxepino[4,5-d]imidazoles
RU2161159C2 (ru) * 1994-11-02 2000-12-27 Жансен Фармасетика Н.В. Замещенные тетрациклические производные оксазепина и тиазепина, способ их получения, композиция, обладающая антипсихотической активностью, и способ ее получения
HRP20000310A2 (en) 2000-05-17 2002-02-28 Pliva Farmaceutska Ind Dioniko New dibenzoazulene compounds as tumor necrosis factor inhibitors
HRP20020304B1 (en) * 2002-04-10 2008-04-30 GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. 1-oxa-3-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the production thereof
HRP20020305A8 (en) * 2002-04-10 2009-03-31 GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. 2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof
US20050131056A1 (en) * 2002-04-10 2005-06-16 Pliva-Istrazivacki Institut D.O.O. 2- thia-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the preparation thereof
HRP20020303B8 (en) * 2002-04-10 2009-03-31 GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. Benzonaphthoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof
HRP20020441A2 (en) * 2002-05-21 2003-12-31 Pliva D D 1-oxa-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediate for preparation thereof
HRP20020440B1 (en) * 2002-05-21 2008-02-29 GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. 1-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the preparation thereof
HRP20020451A2 (en) * 2002-05-23 2003-12-31 Pliva D D 1-tia-3-aza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof
HRP20020453A2 (en) * 2002-05-23 2003-12-31 Pliva D D 1,3-diaza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediate for preparation thereof
HRP20030160A2 (en) * 2003-03-06 2005-04-30 Pliva-Istra�iva�ki institut d.o.o. 1-thiadibenzoazulene derivatives and biological action thereof
HRP20030885A2 (en) * 2003-11-03 2005-08-31 Pliva-Istra�iva�ki institut d.o.o. USE OF 2-THIA-DIBENZO[e,h]AZULENES FOR THE MANUFACTURE OF PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT AND PREVENTION OF CENTRAL NERVOUS SYYTEM DISEASES AND DISORDERS

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Publication number Publication date
BR0309101A (pt) 2005-02-09
EP1492797A1 (de) 2005-01-05
NZ535621A (en) 2006-03-31
DE60304047T2 (de) 2006-11-09
DK1492797T3 (da) 2006-07-17
WO2003084964A1 (en) 2003-10-16
UA79276C2 (en) 2007-06-11
US7232815B2 (en) 2007-06-19
CA2481463A1 (en) 2003-10-16
HRP20020304B1 (en) 2008-04-30
PL372456A1 (en) 2005-07-25
PT1492797E (pt) 2006-07-31
ATE320434T1 (de) 2006-04-15
CN1649878A (zh) 2005-08-03
DE60304047D1 (de) 2006-05-11
ES2260636T3 (es) 2006-11-01
US20050148576A1 (en) 2005-07-07
RU2323222C2 (ru) 2008-04-27
NO20044507L (no) 2004-11-09
AU2003259960A1 (en) 2003-10-20
JP2005529867A (ja) 2005-10-06
HRP20020304A2 (en) 2004-06-30
MXPA04009944A (es) 2005-09-30
IL164397A0 (en) 2005-12-18
IS7473A (is) 2004-09-27
YU88204A (sh) 2006-08-17
RU2004132867A (ru) 2005-05-10

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